{"gene":"TSR1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1996,"finding":"The TSR1 gene product of Yarrowia lipolytica is an essential component involved in the signal recognition particle (SRP)-dependent translocation pathway of secretory proteins through the endoplasmic reticulum; tsr1-1 mutants show 70% reduction in AEP precursor synthesis, and the gene encodes a serine-rich transmembrane protein with an N-terminal signal peptide localized to the ER membrane.","method":"Suppressor genetics, gene cloning/complementation, pulse-chase labeling, immunoprecipitation, gene disruption","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — suppressor genetics with complementation and biochemical phenotype, but in Yarrowia lipolytica (non-mammalian yeast), single lab","pmids":["8798620"],"is_preprint":false},{"year":1997,"finding":"Yarrowia lipolytica Tsr1p is a transmembrane component of the ER membrane that physically interacts (by co-immunoprecipitation) with the ER lumenal chaperone Kar2p, with ribosomal components associated with 5.8S rRNA, and with SRP components Sec65p and 7SL RNA; it also restores SRP stability in an scr2.II-13 mutant context, placing it at the interface of the SRP-ribosome complex and the ER lumen.","method":"Co-immunoprecipitation, co-fractionation, protease protection assay, sedimentation analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and fractionation with multiple binding partners, single lab, yeast model","pmids":["9305926"],"is_preprint":false},{"year":1999,"finding":"Disruption of YHC8 (the S. cerevisiae homologue of Y. lipolytica TSR1) causes accumulation of precursors of multiple soluble secretory proteins (carboxypeptidase Y, alpha-factor, invertase) and a membrane protein (dipeptidyl-aminopeptidase), establishing YHC8/TSR1 family members as direct components of the SRP-dependent ER translocation pathway; Yhc8p localizes to the ER by immunofluorescence.","method":"Gene disruption (null mutation), pulse-chase/immunoprecipitation of secretory protein precursors, immunofluorescence localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple substrate phenotype readouts and direct ER localization, single lab, yeast model","pmids":["10196219"],"is_preprint":false}],"current_model":"Based on yeast ortholog studies, the TSR1 gene family encodes ER transmembrane proteins that function as essential components of the SRP-dependent protein translocation pathway, physically associating with the SRP-ribosome complex (via 7SL RNA and Sec65p), ribosomal components (5.8S rRNA), and the ER lumenal chaperone Kar2p to facilitate co-translational import of secretory proteins into the ER; the mechanistic basis in the human/mammalian protein remains largely uncharacterized by direct experiment in the available literature."},"narrative":{"mechanistic_narrative":"TSR1 family members are essential components of the signal recognition particle (SRP)-dependent pathway that translocates secretory proteins across the endoplasmic reticulum membrane [PMID:8798620, PMID:10196219]. In Yarrowia lipolytica, the TSR1 gene product is a serine-rich ER transmembrane protein with an N-terminal signal peptide, and loss-of-function mutants show severely reduced synthesis of a secretory protein precursor [PMID:8798620]. Mechanistically, Tsr1p sits at the interface between the SRP-ribosome complex and the ER lumen, physically associating with the ER lumenal chaperone Kar2p, with ribosomal components bound to 5.8S rRNA, and with the SRP components Sec65p and 7SL RNA, and it restores SRP stability in an SRP-mutant background [PMID:9305926]. Disruption of the S. cerevisiae homologue YHC8 causes accumulation of precursors of multiple soluble secretory proteins and of a membrane protein, with the protein localizing to the ER, confirming a conserved, direct role in co-translational ER import [PMID:10196219]. The mechanistic basis of the human/mammalian protein has not been characterized by direct experiment in the available corpus.","teleology":[{"year":1996,"claim":"Established that the TSR1 gene product is essential for SRP-dependent secretory protein translocation, answering whether the gene functions in the ER import pathway at all.","evidence":"Suppressor genetics, complementation, pulse-chase labeling and gene disruption in Yarrowia lipolytica, showing 70% reduced precursor synthesis and an ER-membrane serine-rich protein","pmids":["8798620"],"confidence":"Medium","gaps":["Demonstrated only in Yarrowia lipolytica by a single lab","Molecular activity within the translocation reaction not resolved","No direct evidence in mammalian systems"]},{"year":1997,"claim":"Defined the physical interaction network of Tsr1p, answering how it bridges the SRP-ribosome complex and the ER lumen.","evidence":"Reciprocal co-immunoprecipitation, co-fractionation, protease protection and sedimentation analysis in Y. lipolytica identifying Kar2p, ribosomal/5.8S rRNA, Sec65p and 7SL RNA associations and restored SRP stability","pmids":["9305926"],"confidence":"Medium","gaps":["Interactions characterized in a single yeast species by one lab","Stoichiometry and direct vs. indirect nature of each contact unresolved","No structural model of the assembly"]},{"year":1999,"claim":"Showed the role is conserved in S. cerevisiae and affects diverse substrates, answering whether the translocation defect is general across secretory cargo.","evidence":"Gene disruption of YHC8, pulse-chase/immunoprecipitation of multiple secretory precursors, and immunofluorescence localization to the ER","pmids":["10196219"],"confidence":"Medium","gaps":["Demonstrated in yeast only; mammalian ortholog function untested","Mechanism of substrate recognition not established","Position relative to the Sec translocon machinery not defined"]},{"year":null,"claim":"Whether the human/mammalian TSR1 protein performs an analogous role in SRP-dependent ER translocation, and its molecular mechanism, remains uncharacterized by direct experiment.","evidence":"No mammalian functional studies present in the available corpus","pmids":[],"confidence":"Low","gaps":["No direct experimental characterization of the human protein","No structural or biochemical reconstitution of the proposed activity","Conservation of the interaction network in mammals untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["KAR2","SEC65"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q2NL82","full_name":"Pre-rRNA-processing protein TSR1 homolog","aliases":[],"length_aa":804,"mass_kda":91.8,"function":"Required during maturation of the 40S ribosomal subunit in the nucleolus","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q2NL82/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TSR1","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000167721","cell_line_id":"CID001080","localizations":[{"compartment":"nucleolus_gc","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"BYSL","stoichiometry":10.0},{"gene":"LTV1","stoichiometry":10.0},{"gene":"PNO1","stoichiometry":10.0},{"gene":"NOB1","stoichiometry":10.0},{"gene":"RIOK2","stoichiometry":4.0},{"gene":"RIOK3","stoichiometry":4.0},{"gene":"RPS11","stoichiometry":4.0},{"gene":"FAM207A","stoichiometry":4.0},{"gene":"FAU","stoichiometry":4.0},{"gene":"RRP12","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001080","total_profiled":1310},"omim":[{"mim_id":"620074","title":"LTV1 RIBOSOME BIOGENESIS FACTOR; LTV1","url":"https://www.omim.org/entry/620074"},{"mim_id":"618710","title":"PARTNER OF NOB1; PNO1","url":"https://www.omim.org/entry/618710"},{"mim_id":"617754","title":"RIO KINASE 2; RIOK2","url":"https://www.omim.org/entry/617754"},{"mim_id":"617753","title":"RIO KINASE 1; RIOK1","url":"https://www.omim.org/entry/617753"},{"mim_id":"617723","title":"RIBOSOMAL RNA-PROCESSING 12; RRP12","url":"https://www.omim.org/entry/617723"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TSR1"},"hgnc":{"alias_symbol":["FLJ10534"],"prev_symbol":[]},"alphafold":{"accession":"Q2NL82","domains":[{"cath_id":"3.40.50.300","chopping":"73-243","consensus_level":"high","plddt":87.1587,"start":73,"end":243},{"cath_id":"2.40.10.190","chopping":"488-513_695-773","consensus_level":"medium","plddt":93.5531,"start":488,"end":773}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2NL82","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q2NL82-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q2NL82-F1-predicted_aligned_error_v6.png","plddt_mean":80.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TSR1","jax_strain_url":"https://www.jax.org/strain/search?query=TSR1"},"sequence":{"accession":"Q2NL82","fasta_url":"https://rest.uniprot.org/uniprotkb/Q2NL82.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q2NL82/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2NL82"}},"corpus_meta":[{"pmid":"31296287","id":"PMC_31296287","title":"Association of TSR1 Variants and Spontaneous Coronary Artery Dissection.","date":"2019","source":"Journal of the American College of Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/31296287","citation_count":43,"is_preprint":false},{"pmid":"24922194","id":"PMC_24922194","title":"Two splicing factors carrying serine-arginine motifs, TSR1 and TSR1IP, regulate splicing, mRNA stability, and rRNA processing in Trypanosoma brucei.","date":"2014","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/24922194","citation_count":31,"is_preprint":false},{"pmid":"24027350","id":"PMC_24027350","title":"Examining new phylogenetic markers to uncover the evolutionary history of early-diverging fungi: comparing MCM7, TSR1 and rRNA genes for single- and multi-gene analyses of the Kickxellomycotina.","date":"2013","source":"Persoonia","url":"https://pubmed.ncbi.nlm.nih.gov/24027350","citation_count":20,"is_preprint":false},{"pmid":"29891754","id":"PMC_29891754","title":"Recombinant TSR1 of ADAMTS5 Suppresses Melanoma Growth in Mice via an Anti-angiogenic Mechanism.","date":"2018","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/29891754","citation_count":11,"is_preprint":false},{"pmid":"10196219","id":"PMC_10196219","title":"Disruption of YHC8, a member of the TSR1 gene family, reveals its direct involvement in yeast protein translocation.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10196219","citation_count":10,"is_preprint":false},{"pmid":"23683325","id":"PMC_23683325","title":"The WXXW motif in the TSR1 of ADAMTS13 is important for its secretion and proteolytic activity.","date":"2013","source":"Thrombosis research","url":"https://pubmed.ncbi.nlm.nih.gov/23683325","citation_count":9,"is_preprint":false},{"pmid":"8798620","id":"PMC_8798620","title":"The TSR1 gene of Yarrowia lipolytica is involved in the signal recognition particle-dependent translocation pathway of secretory proteins.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8798620","citation_count":6,"is_preprint":false},{"pmid":"32102773","id":"PMC_32102773","title":"Studies of congenital cataract-related TSR1 mutation and its expression in the lens.","date":"2020","source":"Yi chuan = Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/32102773","citation_count":2,"is_preprint":false},{"pmid":"9305926","id":"PMC_9305926","title":"Yarrowia lipolytica TSR1 gene product. A novel endoplasmic reticulum membrane component involved in the signal recognition particle-dependent translocation pathway.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9305926","citation_count":2,"is_preprint":false},{"pmid":"18210152","id":"PMC_18210152","title":"Establishment of thymoma-prone congenic rat strain, ACI.BUF/Mna-Tsr1/Tsr1.","date":"2008","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18210152","citation_count":2,"is_preprint":false},{"pmid":"35762256","id":"PMC_35762256","title":"New missense mutation p.Trp387Ser affecting the functionally important TrpXXTrp motif in the TSR1 repeat of ADAMTS13 metalloproteinase: Case report.","date":"2022","source":"Clinical and experimental pharmacology & physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35762256","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15096,"output_tokens":1448,"usd":0.051822,"retried_sync":true,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7395,"output_tokens":1645,"usd":0.03905,"stage2_stop_reason":"end_turn"},"total_usd":0.090872,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"The TSR1 gene product of Yarrowia lipolytica is an essential component involved in the signal recognition particle (SRP)-dependent translocation pathway of secretory proteins through the endoplasmic reticulum; tsr1-1 mutants show 70% reduction in AEP precursor synthesis, and the gene encodes a serine-rich transmembrane protein with an N-terminal signal peptide localized to the ER membrane.\",\n      \"method\": \"Suppressor genetics, gene cloning/complementation, pulse-chase labeling, immunoprecipitation, gene disruption\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — suppressor genetics with complementation and biochemical phenotype, but in Yarrowia lipolytica (non-mammalian yeast), single lab\",\n      \"pmids\": [\"8798620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Yarrowia lipolytica Tsr1p is a transmembrane component of the ER membrane that physically interacts (by co-immunoprecipitation) with the ER lumenal chaperone Kar2p, with ribosomal components associated with 5.8S rRNA, and with SRP components Sec65p and 7SL RNA; it also restores SRP stability in an scr2.II-13 mutant context, placing it at the interface of the SRP-ribosome complex and the ER lumen.\",\n      \"method\": \"Co-immunoprecipitation, co-fractionation, protease protection assay, sedimentation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and fractionation with multiple binding partners, single lab, yeast model\",\n      \"pmids\": [\"9305926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Disruption of YHC8 (the S. cerevisiae homologue of Y. lipolytica TSR1) causes accumulation of precursors of multiple soluble secretory proteins (carboxypeptidase Y, alpha-factor, invertase) and a membrane protein (dipeptidyl-aminopeptidase), establishing YHC8/TSR1 family members as direct components of the SRP-dependent ER translocation pathway; Yhc8p localizes to the ER by immunofluorescence.\",\n      \"method\": \"Gene disruption (null mutation), pulse-chase/immunoprecipitation of secretory protein precursors, immunofluorescence localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple substrate phenotype readouts and direct ER localization, single lab, yeast model\",\n      \"pmids\": [\"10196219\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Based on yeast ortholog studies, the TSR1 gene family encodes ER transmembrane proteins that function as essential components of the SRP-dependent protein translocation pathway, physically associating with the SRP-ribosome complex (via 7SL RNA and Sec65p), ribosomal components (5.8S rRNA), and the ER lumenal chaperone Kar2p to facilitate co-translational import of secretory proteins into the ER; the mechanistic basis in the human/mammalian protein remains largely uncharacterized by direct experiment in the available literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TSR1 family members are essential components of the signal recognition particle (SRP)-dependent pathway that translocates secretory proteins across the endoplasmic reticulum membrane [#0, #2]. In Yarrowia lipolytica, the TSR1 gene product is a serine-rich ER transmembrane protein with an N-terminal signal peptide, and loss-of-function mutants show severely reduced synthesis of a secretory protein precursor [#0]. Mechanistically, Tsr1p sits at the interface between the SRP-ribosome complex and the ER lumen, physically associating with the ER lumenal chaperone Kar2p, with ribosomal components bound to 5.8S rRNA, and with the SRP components Sec65p and 7SL RNA, and it restores SRP stability in an SRP-mutant background [#1]. Disruption of the S. cerevisiae homologue YHC8 causes accumulation of precursors of multiple soluble secretory proteins and of a membrane protein, with the protein localizing to the ER, confirming a conserved, direct role in co-translational ER import [#2]. The mechanistic basis of the human/mammalian protein has not been characterized by direct experiment in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that the TSR1 gene product is essential for SRP-dependent secretory protein translocation, answering whether the gene functions in the ER import pathway at all.\",\n      \"evidence\": \"Suppressor genetics, complementation, pulse-chase labeling and gene disruption in Yarrowia lipolytica, showing 70% reduced precursor synthesis and an ER-membrane serine-rich protein\",\n      \"pmids\": [\"8798620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Demonstrated only in Yarrowia lipolytica by a single lab\",\n        \"Molecular activity within the translocation reaction not resolved\",\n        \"No direct evidence in mammalian systems\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined the physical interaction network of Tsr1p, answering how it bridges the SRP-ribosome complex and the ER lumen.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, co-fractionation, protease protection and sedimentation analysis in Y. lipolytica identifying Kar2p, ribosomal/5.8S rRNA, Sec65p and 7SL RNA associations and restored SRP stability\",\n      \"pmids\": [\"9305926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interactions characterized in a single yeast species by one lab\",\n        \"Stoichiometry and direct vs. indirect nature of each contact unresolved\",\n        \"No structural model of the assembly\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed the role is conserved in S. cerevisiae and affects diverse substrates, answering whether the translocation defect is general across secretory cargo.\",\n      \"evidence\": \"Gene disruption of YHC8, pulse-chase/immunoprecipitation of multiple secretory precursors, and immunofluorescence localization to the ER\",\n      \"pmids\": [\"10196219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Demonstrated in yeast only; mammalian ortholog function untested\",\n        \"Mechanism of substrate recognition not established\",\n        \"Position relative to the Sec translocon machinery not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the human/mammalian TSR1 protein performs an analogous role in SRP-dependent ER translocation, and its molecular mechanism, remains uncharacterized by direct experiment.\",\n      \"evidence\": \"No mammalian functional studies present in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct experimental characterization of the human protein\",\n        \"No structural or biochemical reconstitution of the proposed activity\",\n        \"Conservation of the interaction network in mammals untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KAR2\", \"SEC65\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}